Amidation of Enones via Beckmann Rearrangement.

The Beckmann reaction is one of the most atom-economical methods for the preparation of amides from ketones. Unlike ketones, the multiple competing reactivities of enones as well as the requirement of demanding reaction conditions for in situ generation of oximes have severely impacted the application of this reaction for the preparation of α,ß-unsaturated amides. Herein, we describe the first chemoselective method for the direct conversion of enones to the corresponding α,ß-unsaturated amides using N-Boc-O-tosylhydroxylamine.

Zirconium oxide nano-catalyzed synthesis of pharmacologically important bis(indolyl)methanes: a highly efficient and mild approach.

We report herein a highly efficient and mild approach for synthesizing pharmacologically active bis(indolyl)methanes 3a-z, utilizing ZrO2 nanoparticles as a catalyst. The method involves a condensation reaction between indole and diverse aromatic aldehydes in acetonitrile under mild conditions. The ZrO2 nano-catalyst prepared via a co-precipitation method demonstrates exceptional efficacy, leading to favourable yields of the target bis(indolyl)methanes 3a-z. The versatility of this methodology is highlighted through substrate screening, showcasing its applicability to various aromatic aldehydes.

Novel ether derivatives of 11-azaartemisinins with high order antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice.

This study investigates cutting-edge synthetic chemistry approaches for designing and producing innovative antimalarial drugs with improved efficacy and fewer adverse effects. Novel amino (-NH2) and hydroxy (-OH) functionalized 11-azaartemisinins 9, 12, and 14 were synthesized along with their derivatives 11a, 13a-e, and 15a-b through ART and were tested for their AMA (antimalarial activity) against Plasmodium yoelii via intramuscular (i.m.) and oral routes in Swiss mice. Ether derivative 13c was the most active compound by i.m. route, it has shown 100 % protection at the dose of 12 mg/kg × 4 days and showed 100 % clearance of parasitaemia on day 4 at dose of 6 mg/kg. Amine 11a, ether derivatives 13d, 13e and ether 15a also showed promising antimalarial activity. ß-Arteether gave 100 % protection at the dose of 48 mg/kg × 4 days and 20 % protection at 24 mg/kg × 4 days dose by oral route, while it showed 100 % protection at 6 mg/kg × 4 days and no protection at 3 mg/kg × 4 days by i.m. route.

Targeting caspase pathway by novel N-Me aziridine derivatives for hepatocellular carcinoma drug discovery.

Azaheterocycles are three-membered rings, known as aziridines, that occur naturally and have pharmaceutical applications.These compounds are present as several secondary metabolites produced by plants and microorganisms.Recent studies have demonstrated the effectiveness of aziridine derivatives (N-H/N-Me) as anticancer agents.We synthesized 18 compounds containing an N-Me enone aziridine group, the chemistry of which has been previously published. However, these compounds have drug-likeness properties; therefore, we aimed to demonstrate their drug-like properties using in silico and in vitro investigations.The molecular structures of the compounds were optimized using density functional theory (DFT). The ADMET parameters of the derivatives were calculated using SwissADME and PreADMET. Additionally, these derivatives were evaluated for their ability to bind to caspase-3 and caspase-9 and then subjected to molecular docking. The lead chemical AY128 maintained stable complexes with target proteins during molecular dynamics simulations, as evidenced by the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) parameters. In vitro cytotoxicity and ELISA tests showed that the novel aziridine derivatives, especially AY128, had strong anticancer activity against HepG2 hepatocellular carcinoma cells.Our study suggests that AY128 may be a potential drug candidate for hepatocellular carcinoma through the caspase-3 and caspase-9-dependent apoptotic pathways.Communicated by Ramaswamy H. Sarma.

Direct N-Me Aziridination of Enones.

The first direct general method for N-Me aziridination of electron-deficient olefins, enones, is described using N-methyl-O-tosylhydroxylamine as the aminating agent in the presence of a Cu(OTf)2 catalyst. The aziridination of vinyl ketones, hitherto unknown for N-Me as well as N-H, has been achieved efficiently. The open-flask reaction is stereospecific, operationally simple, and additive-free. It also efficiently affords N-H aziridinated products under a similar reaction condition.

Stereoselective Oxidative Rearrangement of Disubstituted Unactivated Alkenes Using Hypervalent Iodine(III) Reagent.

The stereoselective oxidative rearrangement of disubstituted unactivated olefins has been achieved using a hypervalent iodine(III) reagent. The aryl group undergoes 1,2-migration to give tert-α-arylated aldehydes (as acetals). The preparation of these aldehydes/acetals, especially containing a tert-benzylic stereocenter, has remained challenging. This migration-based method provides a complementary approach over the known α-substitution-based methods for accessing this class of molecules.

Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6/COX-2 mediated JAK2/STAT3 signals as evidenced through data-based mathematical modeling.

We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through 1H NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.

Cu(OTf)2-catalyzed Beckmann Rearrangement of Ketones Using Hydroxylamine-O-sulfonic Acid (HOSA).

The Beckmann Rearrangement (BKR) of ketones to secondary amides often requires harsh reaction conditions that limit its practicality and scope. Herein, we describe the Cu(OTf)2-catalyzed BKR of ketones under mild reaction conditions using hydroxylamine-O-sulfonic acid (HOSA), a commercial water soluble aminating agent. This method is compatible with most functional groups and directly provides the desired amides in good to excellent yields.

Current scenario of artemisinin and its analogues for antimalarial activity.

Human malaria, one of the most striking, reemerging infectious diseases, is caused by several types of Plasmodium parasites. Whilst advances have been made in lowering the numbers of cases and deaths, it is clear that a strategy based solely on disease control year on year, without reducing transmission and ultimately eradicating the parasite, is unsustainable. Natural products have served as a template for the design and development of antimalarial drugs currently in the clinic or in the development phase. Artemisinin combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. The alkylating ability of artemisinin and its semi-synthetic analogues toward heme related to their antimalarial efficacy are underlined. Although impressive results have already been achieved in malaria research, more systematization and concentration of efforts are required if real breakthroughs are to be made. This review will concisely cover the clinical, preclinical antimalarial and current updates in artemisinin based antimalarial drugs. Diverse classes of semi-synthetic analogs of artemisinin reported in the last decade have also been extensively studied. The experience gained in this respect is discussed.

Direct N-H/ N-Me Aziridination of Unactivated Olefins Using O-(Sulfonyl)hydroxylamines as Aminating Agents.

Unactivated aziridines are the core substructures in a plethora of bioactive natural products and serve as building blocks in organic synthesis. Despite this, very limited methods are available to access them directly from olefins, as most of the known methods are devoted to their activated counterparts. Herein, we have developed a highly efficient Rh(II)-catalyzed method for the direct preparation of unactivated aziridines from olefins using O-(sulfonyl)hydroxylamines as the aminating agent. The reactions proceed with a high stereospecificity.

O-Substituted hydroxyl amine reagents: an overview of recent synthetic advances.

Reagents derived from hydroxylamines such as 2,4-dinitrophenylhydroxylamine (DPH), O-(diphenylphosphinyl)hydroxylamine (DPPH), hydroxylamine-O-sulfonic acid (HOSA) and other related reagents in which oxygen is substituted with good leaving groups recently showed remarkable potential as electrophilic aminating agents and as a source of the amino group. They facilitate stereo- and regioselective C-N, N-N, O-N, and S-N bond-formation reactions and intra-molecular cyclizations without the requirement of expensive metal catalysts. In this review we have discussed the important transformations achieved with these reagents.

Regio- and enantioselective catalytic monoepoxidation of conjugated dienes: synthesis of chiral allylic cis-epoxides.

Ti(IV)-salan 4 catalyzes the diastereo- and enantioselective monoepoxidation of conjugated dienes using 30% H2O2 at rt or below even in the presence of other olefins and adjacent stereocenters. Its enantiomer, ent-4, provides access to the opposite diastereomer or enantiomer. The resultant chiral allylic epoxides, and the triols derived from them, are versatile synthetic intermediates as well as substructures present in many bioactive natural products. The epoxidation is highly specific for Z-olefins. For 1-acyl(silyl)oxypenta-2,4-dienes, epoxidation of the distal olefin is generally favored in contrast to the adjacent regioselectivity characteristic of Sharpless, peracid, and other directed epoxidations of hydroxylated dienes.

Regio- and stereoselective monoepoxidation of dienes using methyltrioxorhenium: synthesis of allylic epoxides.

Methyltrioxorhenium (MTO) complexed with pyridine was shown to be a highly effective catalyst for the regioselective monoepoxidation of conjugated di- and trienes using 30% H2O2 at or below room temperature. The resultant allylic epoxides, and the triols derived from them, are versatile synthetic intermediates as well as substructures present in many bioactive natural products. The site of epoxidation was dependent upon olefin substitution, olefin geometry (Z vs E), and the presence of electron-withdrawing substituents on adjacent carbons. For 1-acyl(silyl)oxypenta-2,4-dienes, epoxidation of the distal olefin was generally favored in contrast to the adjacent regioselectivity characteristic of Sharpless, peracid, and other directed epoxidations of hydroxylated dienes.

Direct stereospecific synthesis of unprotected N-H and N-Me aziridines from olefins.

Despite the prevalence of the N-H aziridine motif in bioactive natural products and the clear advantages of this unprotected parent structure over N-protected derivatives as a synthetic building block, no practical methods have emerged for direct synthesis of this compound class from unfunctionalized olefins. Here, we present a mild, versatile method for the direct stereospecific conversion of structurally diverse mono-, di-, tri-, and tetrasubstituted olefins to N-H aziridines using O-(2,4-dinitrophenyl)hydroxylamine (DPH) via homogeneous rhodium catalysis with no external oxidants. This method is operationally simple (i.e., one-pot), scalable, and fast at ambient temperature, furnishing N-H aziridines in good-to-excellent yields. Likewise, N-alkyl aziridines are prepared from N-alkylated DPH derivatives. Quantum-mechanical calculations suggest a plausible Rh-nitrene pathway.

Androgen-dependent hypertension is mediated by 20-hydroxy-5,8,11,14-eicosatetraenoic acid-induced vascular dysfunction: role of inhibitor of kappaB Kinase.

Increased vascular synthesis of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) is associated with increased vascular contraction, endothelial dysfunction, and endothelial activation; all are believed to account for 20-HETE prohypertensive properties. We demonstrated previously that the 20-HETE-dependent inhibition of NO production is mediated through inhibitor of κB kinase (IKK), suggesting a cross-talk between 20-HETE-mediated endothelial dysfunction and activation. In this study, we examined the temporal relationship among blood pressure, endothelial dysfunction, and endothelial activation and the role of IKK in the rat model of androgen-driven 20-HETE-mediated hypertension. In Sprague-Dawley rats treated with 5α-dihydrotestosterone, renal vascular 20-HETE levels increased by day 2 of treatment from 17.7±2.4 to 57.7±9.7 ng/mg, whereas blood pressure elevation reached significance by day 3 (132.7±1.7 versus 117.2±0.8 mm Hg). In renal interlobar arteries, when compared with vehicle, 5α-dihydrotestosterone treatment increased the sensitivity to phenylephrine-induced vasoconstriction by 3.5-fold, decreased acetylcholine-induced vasorelaxation, and increased nuclear factor κB activity, all of which were attenuated by treatment with the 20-HETE antagonist, 20 hydroxyeicosa-6(Z),15(Z)-dienoic acid, (20-6,15-HEDE). Cotreatment with parthenolide, an IKK inhibitor, attenuated the androgen-dependent 20-HETE-mediated elevation in blood pressure (from 133.7±3.1 to 109.8±3.0 mm Hg). In addition, parthenolide treatment negated 20-HETE-mediated inhibition of the relaxing response to acetylcholine and 20-HETE-mediated increase in vascular nuclear factor κB activity. These findings suggest that inhibition of IKK attenuates the androgen-dependent 20-HETE-mediated increase in blood pressure by inhibiting both 20-HETE-dependent endothelial activation and dysfunction.